Is ERBB2 p.Pro489Leu (c.1466C>T) pathogenic?

ERBB2 p.Pro489Leu (c.1466C>T) is classified Conflicting classifications of pathogenicity in ERBB2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.1386); Rare (popmax 0.214%, mid); Associated with glioma susceptibility 1.

What condition is associated with ERBB2 p.Pro489Leu (c.1466C>T)?

ERBB2 p.Pro489Leu (c.1466C>T) is associated with glioma susceptibility 1, gastric cancer, ovarian cancer (ClinVar).

How common is ERBB2 p.Pro489Leu (c.1466C>T) in the general population?

ERBB2 p.Pro489Leu (c.1466C>T) is rare (popmax 0.214%, mid) (gnomAD).

What do computational predictors say about ERBB2 p.Pro489Leu (c.1466C>T)?

AlphaMissense predicts likely benign (score 0.1386) — an in-silico prediction, not a clinical call.

ERBB2 p.Pro489Leu

c.1466C>T · rs142456637 · VCV134071

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1386 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

glioma susceptibility 1

Computational evidence

Protein change
AlphaMissense	0.1386	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 16 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% Middle Eastern · 13/6,062 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0732% 1,180/1,612,320 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	466
Remaining individualsnot grpmax-eligible	0.114%	880
Admixed American	0.0983%	1,017
European (non-Finnish)	0.085%	1,176
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
African / African-American	0.012%	8,340
Finnishnot grpmax-eligible	0.00482%	20,727
South Asian	0.00329%	30,359
East Asian	0.00223%	44,874

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERBB2
Protein: p.Pro489Leu
Coding: c.1466C>T
MANE Select: NM_004448
dbSNP: rs142456637
Type: single nucleotide variant
Location: chr17:39715892 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 489: a β-strand; a disulfide bond

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glioma susceptibility 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer ovarian cancer lung cancer visceral neuropathy, familial, 2, autosomal recessive

Similar variants

ERBB2 p.Pro489= Benign/Likely benign ★★ same residue
ERBB2 p.Pro489Ser Uncertain significance ★ ⚠ same residue
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same condition
ERBB2 p.Arg217Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erbb2-p-pro489leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown